Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial.

Abstract

BACKGROUND:

Class II histone deacetylase (HDAC) inhibitors induce hypoxia-inducible factor-1 and -2α degradation and have antitumour effects in combination with vascular endothelial growth factor (VEGF) inhibitors. In this study, we tested the safety and efficacy of the HDAC inhibitor vorinostat and the VEGF blocker bevacizumab in metastatic clear-cell renal cell carcinoma (ccRCC) patients previously treated with different drugs including sunitinib, sorafenib, axitinib, interleukin-2, interferon, and temsirolimus.

METHODS:

Patients with up to two prior regimens were eligible for treatment, consisting of vorinostat 200 mg orally two times daily × 2 weeks, and bevacizumab 15 mg kg-1 intravenously every 3 weeks. The primary end points were safety and tolerability, and the proportion of patients with 6 months of progression-free survival (PFS). Correlative studies included immunohistochemistry, FDG PET/CT scans, and serum analyses for chemokines and microRNAs.

RESULTS:

Thirty-six patients were enrolled, with 33 evaluable for toxicity and efficacy. Eighteen patients had 1 prior treatment, 13 patients had 2 prior treatments, and 2 patients were treatment naïve. Two patients experienced grade 4 thrombocytopenia and three patients had grade 3 thromboembolic events during the course of exposure. We observed six objective responses (18%), including one complete response and five partial responses. The proportion of patients with PFS at 6 months was 48%. The median PFS and overall survival were 5.7 months (confidence interval (CI): 4.1-11.0) and 13.9 months (CI: 9.8-20.7), respectively. Correlative studies showed that modulation of specific chemokines and microRNAs were associated with clinical benefit.

CONCLUSIONS:

The combination of vorinostat with bevacizumab as described is relatively well tolerated. Response rate and median PFS suggest clinical activity for this combination strategy in previously treated ccRCC.

• Authors: Roberto Pili, Glenn Liu, Sreenivasulu Chintala, Hendrick Verheul, Shabnam Rehman, Kristopher Attwood, Martin A Lodge, Richard Wahl, James I Martin, Kiersten Marie Miles, Silvia Paesante, Remi Adelaiye, Alejandro Godoy, Serina King, James Zwiebel, Michael A Carducci
• Journal: British journal of cancer (Br J Cancer) Vol. 116 Issue 7 Pg. 874-883 (Mar 28 2017) ISSN: 1532-1827 [Electronic] England
• PMID: 28222071 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study)

Chemical References

• Biomarkers, Tumor
• Cytokines
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• MicroRNAs
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Bevacizumab
• Vorinostat

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bevacizumab (administration & dosage)
• Biomarkers, Tumor (blood)
• Carcinoma, Renal Cell (blood, drug therapy, genetics, pathology)
• Cytokines (blood)
• Female
• Follow-Up Studies
• Histone Deacetylase Inhibitors (therapeutic use)
• Humans
• Hydroxamic Acids (administration & dosage)
• Immunoenzyme Techniques
• Kidney Neoplasms (blood, drug therapy, genetics, pathology)
• Male
• MicroRNAs (blood, genetics)
• Middle Aged
• Neoplasm Staging
• Prognosis
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)
• Vorinostat